Premature birth or preterm delivery (PTD) is defined as any delivery occurring before 37 weeks of gestation. PTD is an undesirable complication of pregnancy responsible for a variety of impairments in the newborn baby due to lower birth weight, motor and cognitive disabilities, and, in very severe cases, in-partum or after partum death. In cases of pregnancy complications, maintaining pregnancy for the full term (37-41 weeks) is important for two major reasons. One is to allow the pregnant woman to reach a tertiary level medical center before birth, an issue of great significance in community clinics and rural-based health service settings. The other is to buy time to administer treatments and drugs such as antenatal corticosteroids that facilitate the maturation of fetal organs. There is therefore a need in certain cases to extend pregnancy duration so as to reduce the severity of the consequences of pre-maturity.
Tocolytics are a group of medications clinically utilized to stop contractions, thereby reducing the risk of PTD. Tocolytics delay parturition and thus decrease prenatal mortality and morbidity. Evidence has been reported that tocolytics delay delivery by 1-7 days, thus allowing for a significant time to administer drugs such as antenatal corticosteroids. Tocolytics are routinely administrated when a pregnant woman with gestational age between 20 and 37 weeks (confirmed by dating the gestational age according to the last menstrual period or by ultrasound) has frequent, regular uterine contractions (preferably documented by a tocodynamonmeter) and/or when she shows progressive change in the cervix or a cervical dilation greater than 2 cm and effacement greater than 80%. However, tocolytics may have adverse effects either directly or as a result of inappropriate prolongation of pregnancy in an adverse intrauterine environment, e.g. uterine abruption. The prophylactic use of tocolytic agents can be associated with side effects such as maternal pulmonary edema, especially in women carrying twins, chorioamnionitis, and dehydration. Placenta abruption and intrauterine growth restriction are among the contra-indications for the use of tocolytic agents.
In all cases of patients at gestation week 34-37, any of the above symptoms will indicate initiation of treatment, adjusted individually to each patient. For patients of less than 34 weeks, where a risk for preterm labor is identified early, tocolytic agents are often given 2-4 times prophylactically from 32-34 weeks of gestation, subject to laboratory testing indicating it is allowed. During tocolytic agent administration it is necessary to continuously monitor fetal heart rate and uterine activity, pulmonary status, cardiovascular status, glucose level and clotting factors; Ultrasound is required to confirm date and rule out anomalies, pelvic exam is made to confirm cervical status, and laboratory studies including CBC, urine for culture and sensitivity follow the health status while group B beta hemolytic strep culture or rapid identification test are carried out. In rare cases, amniocentesis is done in febrile patients.
A number of tocolytic agents have been used in the clinic. Initially, the beta agonists (beta mimetic), especially ritodrine and terbutaline, were extensively used, but were found to have adverse maternal side effects.
The calcium channel blockers came next. These included the following:
A. Magnesium Sulfate (MgSO4)—Neonatal neuromuscular blockade and difficult resuscitation may be associated with excessive use of magnesium sulfate. In addition, there are conflicting data as to the neuroprotective effect of magnesium sulfate. Despite the debate of the efficacy of MgSO4 and its side effects, it remains the first-line tocolytic agent in many institutions.
B. Nifedipine is associated with a greater chance of delivery delay, less maternal side effects and less neonatal respiratory distress syndrome than the beta agonists. There is a theoretical risk to the fetus, based on animal studies, although human clinical studies have so far failed to show a similar result.
Another group of tocolytics are non-steroidal anti-inflammatory drugs (NSAID) such as indomethacin and glyceryl-tri-nitrite which have fewer side effects and better efficacy as measured by lowering the occurrence of low birth weight and prolonging pregnancy. Due to the slow effect of indomethacin, it is often given together with a tocolytic of one of the other groups. The oxytocin antagonist, atosiban, has a comparable effect on delivery delay to the beta agonists but with fewer maternal side effects. Its relatively higher price limits its wide use clinically.
Many of the side effects related to the administration of tocolytics, either given i.v, or per-os, are related to the damage they cause to the placenta, such as facilitated apoptosis, damage to maternal artery blood flow and the level of placental tissue oxidation and nutrition. In some cases, the damage to the placenta can lead to several complications and exacerbate conditions such as intrauterine growth restriction (IUGR). There is no method currently available to detect the impact of tocolytic agents on the placenta, and thereby on the fetus and the mother.
Thus, a balance must be struck between administrating a too high dose of tocolytics, which can damage the placenta, fetus and/or mother, and a too low dose which will not be effective in preventing PTD. It is therefore desirable to have a means for monitoring the effect of a specific type and dose of tocolytics on the pregnant woman.
U.S. Pat. No. 5,370,135 discloses a method for monitoring the efficacy of tocolytic treatments by monitoring estriol concentrations in a body fluid before or during treatment with a tocolytic agent. A first concentration of estriol is measured in a body fluid of a pregnant patient undergoing or diagnosed as a candidate for undergoing treatment with a tocolytic agent, and is correlated with a predetermined standard estriol value. Analysis of the correlation allows a physician to reach better decisions on whether to begin or continue the tocolytic treatment or whether the treatment should be discontinued or modified.
Placental Protein 13 (PP13) is a protein of 15-16,000 MW which may be purified from human placental tissue or prepared by recombinant technology as described in U.S. Pat. No. 6,548,306 (Admon, et al), the contents of which are incorporated herein by reference. Purified PP13 was used to develop an assay for the detection of some pregnancy-related disorders such as intrauterine growth restriction (IUGR), preeclampsia and preterm delivery as described in U.S. Pat. No. 5,198,366 (Silberman), the contents of which are incorporated herein by reference. Both a radioimmunoassay (RIA) and an enzyme-linked immunosorbent assay (ELISA) were developed using labeled PP13 and anti PP13 polyclonal antiserum.
Amino acid composition and sequence analysis of PP13 revealed highest homology to the galectin family—a group of proteins with high affinity to sugar residues which is particularly important in bridging cells to the extracellular matrix (and in differentiation) (Than, N. G., et al (1999) Placenta 20:703-710; Than, et al., (2004) Eur. J Biochem. 271(6):1065-1078). Indeed PP13 was found by immunohistochemistry to be important in placentation.
U.S. Pat. No. 6,790,625 discloses monoclonal antibodies to PP13 and a solid-phase immunoassay capable of measuring maternal serum PP13 during the early stages of pregnancy.
WO 04/021012 discloses a diagnostic method for pregnancy complications based on a number of factors, including PP13 level.